Fuel cells (FCs) convert chemical energy into electricity through electrochemical reactions. They maintain desirable functional advantages that render them as attractive candidates for renewable energy alternatives. However, the high cost and general scarcity of conventional FC catalysts largely limit the ubiquitous application of this device configuration. For example, under current consumption requirements, there is an insufficient global reserve of Pt to provide for the needs of an effective FC for every car produced. Therefore, it is absolutely necessary in the future to replace Pt either completely or in part with far more plentiful, abundant, cheaper, and potentially less toxic first row transition metals, because the high cost-to-benefit ratio of conventional catalysts is and will continue to be a major limiting factor preventing mass commercialization. We and other groups have explored a number of nanowire-based catalytic architectures, which are either Pt-free or with reduced Pt content, as an energy efficient solution with improved performance metrics versus conventional, currently commercially available Pt nanoparticles that are already well established in the community. Specifically, in this Perspective, we highlight strategies aimed at the rational modification of not only the physical structure but also the chemical composition as a means of developing superior electrocatalysts formore » a number of small-molecule-based anodic oxidation and cathodic reduction reactions, which underlie the overall FC behavior. In particular, we focus on efforts to precisely, synergistically, and simultaneously tune not only the size, morphology, architectural motif, surface chemistry, and chemical composition of the as-generated catalysts but also the nature of the underlying support so as to controllably improve performance metrics of the hydrogen oxidation reaction, the methanol oxidation reaction, the ethanol oxidation reaction, and the formic acid oxidation reaction, in addition to the oxygen reduction reaction.« less